MindMed Investigating Use of Psychedelics to Treat Chronic Pain

By Pat Anson, PNN Editor

A startup pharmaceutical company has announced plans to investigate the use of LSD and other psychedelics to treat chronic pain.

New York-based Mind Medicine (MindMed) is exploring the use of psychedelics to treat two pain conditions, which it is calling “Project Angie.” The company is already investigating the use of psychedelics to treat addiction, anxiety and attention deficit hyperactivity disorder (ADHD).

"With the launch of Project Angie, we seek to align closely with MindMed's core mission to improve mental health and combat substance use for the many patients in need. If we can help to develop a new paradigm to treat pain, it may have the potential to greatly reduce the use of addictive medicines such as opioids currently ravaging society and its mental health," MindMed CEO & Co-Founder J.R. Rahn said in a statement.

MindMed did not disclose what pain conditions it was developing treatments for, but it is working with researchers in Switzerland who have a Phase 2 clinical trial underway on the use of LSD to treat cluster headache. The company said it is also evaluating a second indication for a “common, often debilitating, chronic pain syndrome.”

Interest in using psychedelics to treat medical conditions has been growing in recent years. Preliminary research suggests that microdoses of LSD, psilocybin (magic mushrooms) and other psychedelics may offer a new way to treat pain. The exact mechanism in which psychedelics have an analgesic effect is not fully understood, but early research indicates that LSD can modulate serotonin receptors that help regulate pain and inflammation.

"Evidence dating back to the 1950s suggests that LSD and other psychedelics may have analgesic effects, but this treatment area remains largely untapped by companies studying psychedelics, with the majority of research focusing solely on psychiatric indications," said Rob Barrow, MindMed’s Chief Development Officer. 

The company is planning to submit a Pre-Investigational New Drug (IND) application to the Food and Drug Administration for a Phase 2a proof of concept study of LSD (lysergic acid diethylamide) in the second half of 2021.

MindMed will have to clear some high regulatory hurdles. LSD, psilocybin, MDMA (Ecstasy) and other psychedelics are classified as Schedule I controlled substances, meaning they have a high potential for abuse and currently have no accepted medical use in the United States.

LSD Won’t Make a Good Painkiller

By Roger Chriss, PNN Columnist

Recent news that a small pilot study found LSD has a “protracted analgesic effect” at low doses garnered a lot of enthusiasm and hype. Headlines declared that LSD “could replace opiates” and be a “potent weapon against pain.”

The study looked at two dozen healthy volunteers given low doses of LSD or a placebo and then subjected them to a “cold pressor test” – immersing a hand in near-freezing water. Researchers found that 20 micrograms of LSD “significantly increased the time that participants were able to tolerate exposure to cold (3°C) water.”

Despite this, LSD has a clear problem: Its therapeutic index is very low.

The therapeutic index is a measure of the relative safety of a drug, computed by dividing the toxic dose by the dose needed for a therapeutic response. A toxic dose represents a threshold beyond which undesirable side effects or adverse events become common.

A high therapeutic index is better. It signifies a broader range of possible doses, letting clinicians adjust a dose precisely for a specific patient. Body weight, age, gender and metabolic status all influence drug metabolism and a high therapeutic index improves clinical safety.

A high therapeutic index also means that the drug can be given in multiple doses. If an initial dose is inadequate, a second dose can be given. Or a dose of another medication from the same class can be given. Or the drug can be given repeatedly over a short time without risky cumulative effects. All of this is important, because acute pain associated with trauma, injury or surgery may last for days.

The therapeutic dose of LSD in the simulated pain study was 20 micrograms (lower doses were ineffective). In general, a hallucinogenic dose starts at 25 micrograms. This suggests that LSD’s therapeutic index is 1.25.

Other measures of drug safety look even worse. The measure known as the margin of safety looks at how a dose may be toxic for 1% of people while being clinically effective for the other 99 percent. This accounts for variations in dose-response curves. Since some people experience LSD’s psychoactive effects at well below the standard 25 microgram threshold, LSD’s margin of safety is also very low.

LSD probably has little future as an over-the-counter analgesic or in a standard clinical setting for acute or chronic pain. It may instead have potential as a narrow therapeutic index (NTI) drug, which the FDA defines as a drug “where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity.”

Current NTI drugs include lithium and methotrexate, which are used to treat serious conditions such as bipolar disorder and rheumatoid arthritis in carefully selected patients under close medical supervision. LSD could wind up being designated as an NTI drug, but only if clinical trials demonstrate safety and efficacy in the management of specific types of pain.

In general, however, LSD is unlikely to be a broadly useful analgesic. Pain relievers need to have a wide therapeutic index in order to succeed, and there seems to be no practical way to do this with LSD.

Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research. 

Can LSD Be Used to Treat Pain?

By Roger Chriss, PNN Columnist

The well-known hallucinogen LSD may have a new use. A new study published in the Journal of Psychopharmacology found evidence that LSD exerts a “protracted analgesic effect” at low doses.

The study was performed in The Netherlands on 24 healthy volunteers. Three low doses of LSD or placebo were given to the participants, who immersed a hand in near freezing water 90 minutes and five hours after dosing to assess their pain tolerance.

Results from the “Cold Pressor Test” showed that 20 micrograms of LSD “significantly increased the time that participants were able to tolerate exposure to cold (3°C) water and decreased their subjective levels of experienced pain and unpleasantness.”

It is not clear how or why LSD increased tolerance to cold water. The study authors speculate about LSD’s various actions on serotonin receptors, but also note that “an additional or alternative explanation for the analgesic effects of LSD could be hypertension-associated hypoalgesia.”

There were side effects from LSD, even at low doses. LSD slightly raised blood pressure and increased feelings of dissociation, anxiety and somatization in the volunteers. Psychological and cognitive effects were described as “very mild.”

The study has other important limitations. The Cold Pressor Test is not a good analog for real-world acute pain. And healthy volunteers in such studies tend not to be typical of the population at large. They skew young, male, and often have prior experience with the substance being evaluated that most people do not have.

Also, these studies tend not to translate to real-world use. Recent work on LSD microdosing has found “few benefits and significant downsides.”

Findings Hyped

Unfortunately, this preliminary study has already led to hype about the analgesic potential of LSD. New Atlas called it  “an incredible, first-of-its kind trial” and Futurism reported that LSD microdoses were “as effective as opioids at treating pain.”  Interesting Engineering predicted there could be possible applications of LSD as a non-addictive pain medication.”

The Beckley Foundation, which funded the study, fed the hype with a news release that claimed the analgesic effects of LSD were “remarkably” similar to oxycodone and morphine, but without the risk of addiction.

The present data suggests low doses of LSD could constitute a useful pain management treatment option that is not only effective in patients but is also devoid of the problematic consequences associated with current mainstay drugs, such as opioids,” said Amanda Feilding, Founder and Director of the Beckley Foundation. “We must continue to explore this with the aim of providing safer, non-addictive alternatives to pain management, and to bring people in pain a step closer to living happier, healthier and fully expressed lives.”

Misunderstanding Pain Research

The Cold Pressor Test is a standard way to assess pain threshold and tolerance. But results in the test vary significantly with water temperature, and the test is not seen as a precise analog with real-world pain. As a 2016 review noted, “No single experimental model can mimic the complex nature of clinical pain.”

Pain is a biopsychosocial phenomenon involving a long chain of interactions that start with peripheral sensory nerve endings and manifest in the conscious mind. Analgesic effect can be achieved locally in nerve endings, as seen with lidocaine injections; or intermediately in the spinal cord, as seen with radio frequency ablation or spinal cord simulators; or centrally in the brain, as seen with psychoactive drugs.

Therefore, comparing analgesic efficacy is far more complex than just looking at outcomes in a simple lab-induced pain model in a handful of healthy people. The LSD study did not test its subjects with multiple substances or combinations of substances.

Further, analgesics have to be safe and effective. Safety includes understanding possible drug-drug interactions. A 2008 review noted that “lithium and some tricyclic antidepressants have also been reported to increase the effects of LSD.”

A 2019 study describes several important biochemical pathways and gene polymorphisms in LSD metabolism, possibly affecting pharmacokinetics and pharmacodynamics. The article concludes that “drug-drug interaction studies in humans are required to further assess the clinical relevance of these findings.”

Analgesics like acetaminophen have relatively few drug-drug interactions. Opioids have a number of important ones, but these are well-understood and can be controlled. By contrast, cannabis is messy. Drugs.com lists 24 major and 353 moderate interactions for cannabis. There is no such list for LSD.

Pain medication needs to be effective as well as safe and reliable. Demonstrating efficacy requires far more than a handful of willing subjects being subjected to a simulated pain experience in a laboratory setting. Demonstrating safety and reliability will require extensive testing, pharmacodynamic studies, and research on drug-drug interactions. LSD may have taken the first step toward becoming an analgesic, but there is a long road ahead.

Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research. 

 

Magic Mushrooms, Psychedelics and Chronic Pain

By Roger Chriss, PNN Columnist

The recent news that Denver has decriminalized “magic” mushrooms is the latest sign of growing interest in the use of psychedelics. Whether it’s microdosing mushrooms to stimulate the mind or using them to treat depression and chronic pain, psychedelic drugs are having a moment.

Magic mushrooms are any of roughly 200 different types of fungi that produce psilocybin, a hallucinogenic substance. Other psychedelics include LSD, DMT, ayahuasca and ibogaine. For reasons of chemistry and cultural baggage, DMT is generally avoided, LSD is used with extra caution and psilocybin is getting the most attention in clinical studies.

Preliminary research has found positive outcomes for psychedelic therapy in smoking cessation,  anxiety, post-traumatic stress disorder and refractory depression. And there are promising findings on psychedelics for cluster headaches and phantom limb pain.

A 2015 review in the Journal of Psychoactive Drugs reported that for patients with cluster headaches, psilocybin and other hallucinogens “were comparable to or more efficacious than most conventional medications.”  

In a 2006 Neurology review, researchers interviewed 53 cluster headache patients who used LSD or psilocybin. Most reported success in stopping cluster attacks and extending periods of remission.

And a 2018 Neurocase report described positive results for one patient with intractable phantom pain who combined psilocybin with mirror visual-feedback.

Obviously, these studies are very preliminary. Patient self-reports on drug use outside of clinical settings have limited value as evidence of efficacy. And case reports are by definition too small-scale to generalize from.

Fortunately, more clinical trials are underway for psilocybin and LSD. Last year the FDA approved a “landmark” psilocybin trial for treatment-resistant depression. And the Multidisciplinary Association for Psychedelic Studies is also working to promote robust clinical research.

Of course, psychedelics are not without risks. As described in detail in the book DMT: The Spirit Molecule, patients need to be screened and monitored before, during and after psychedelic therapy.

Michael Pollan, author of “How to Change Your Mind”, told The New York Times that psilocybin has risks “both practical and psychological, and these can be serious.”

There are also risks of conflating the pop culture phenomenon of microdosing to clinical benefits obtained under medical supervision.

The “betterment of healthy people” through microdosing is enthusiastically endorsed in books like “A Really Good Day” by Ayelet Waldman. But a 2018 placebo-controlled study on LSD microdosing found no “robust changes” in perception, mental acitivty or concentration.

The microdosing trend could stymie serious research and bias public opinion about psychedelics — just as it did in the 1960’s.

The potential for psychedelic therapy in the management of chronic pain disorders is two-fold. First, psychedelics may represent a safe and effective way to manage otherwise intractable disorders like cluster headaches and phantom limb pain. Second, psychedelics may help address the depression, PTSD and anxiety that often contribute to or accompany such disorders.

It is to be hoped that more research on psychedelics comes quickly.

Roger Chriss lives with Ehlers Danlos syndrome and is a proud member of the Ehlers-Danlos Society. Roger is a technical consultant in Washington state, where he specializes in mathematics and research.

The information in this column should not be considered as professional medical advice, diagnosis or treatment. It is for informational purposes only and represents the author’s opinions alone. It does not inherently express or reflect the views, opinions and/or positions of Pain News Network.